Prevention of Alzheimer’s Disease?

There is much talk about disease prevention these days, whether it involves changing lifestyle (stopping smoking, losing weight, exercising) or minimizing risk factors (lowering cholesterol, keeping blood pressure lower, or treating diabetes). In other instances, healthy people take medication to prevent something from happening. For example, millions of women have taken contraceptive pills to avoid pregnancy. Recently there have been attempts to avoid HIV by starting anti-HIV drugs while people are still HIV-negative. In a recent New York Times article, Pam Belluck reports the plan for a trial of a drug to prevent the progression of Alzheimer’s in people who are at risk for the disease but are presently quite healthy.

Alzheimer’s disease starts as a pathological process many years before it starts to produce changes in cognitive functions, such as memory. Ideally, if one wanted to prevent the progression of the disease, then this prodromal phase, while patients are still healthy, would be the time to treat it—that is, before they develop brain changes which may be irreversible.

But how do we decide whom to treat and what drugs to use? In order to design an efficient trial, one would like to have a predictable population with a high probability of progressing to symptomatic disease. This upcoming trial takes advantage of just such a rare group: an extended family in Medellin, Colombia, with more than 5,000 members who have a genetically determined form of Alzheimer’s. This inheritance is determined by a mutant gene that is expressed as dominant—meaning if you have the gene, you will get the disease.

The resulting disease is quite predictable: It starts relatively early (people are in their 40s) and progresses rapidly (by their mid-50s they are quite impaired). This population in Colombia was discovered and characterized over many years by Dr. Francisco Lopera. For the last 3-5 years, Drs. Eric Reiman and Pierre Tariot of the Banner Alzheimer’s Institute in Phoenix, working with Dr. Lopera, have designed a preventive study, educated this family about what they are trying to do, and received funding from the National Institutes of Health (NIH) and from other sources, particularly from Genentech, which is also supplying the medication to be used, Crenezumab.

This study will involve 300 people; 100 with the mutant gene will receive Crenezumab, 100 with the mutant gene will receive a placebo, and 100 from the community who don’t have the mutant gene will also receive the placebo. Subjects will be seen at intervals by investigators who will not know which treatment group they are in, assaying their health as well as looking at potential biomarkers of Alzheimer’s. These biomarkers will include brain scans to detect amyloid and changes in brain size and activity, and studies of cerebrospinal fluid to detect changes in the proteins amyloid or tau. If biomarkers move toward normal in the treatment group, does that predict subsequent improvement in clinical outcome? If so, this knowledge could mean future clinical trials that could be shorter and require fewer subjects.

We still don’t know how to effectively treat someone with Alzheimer’s disease. For this trial, as well, there were some particular problems. First, researchers wanted to have a drug that had a chance to work. This is a very unique population, and it may not agree to another research project if this one doesn’t work. Second, this drug is being given to healthy people, so side-effects should be minimal. More than 20 possible drugs were considered before Crenezumab was chosen. One of the theories for the mechanism of Alzheimer’s is the “amyloid hypothesis,” which suggests that the toxic compound is beta-amyloid, a component of the plaques that are characteristic of the pathology of the Alzheimer’s brain. Crenezumab is an antibody that gets into the brain, binds to amyloid, and removes it from the brain. It has been successful in treating animals with a version of Alzheimer’s disease. A secondary outcome of this planned study will be to determine if the amyloid hypothesis is correct. In other words, if amyloid is removed from the brain, will patients get better, or in this case, not progress to dementia?

It is possible that there will be only one shot at studying this unique population. There are much smaller families in the United States who could also be involved in similar studies, but the logistics involved in recruiting enough subjects from these smaller families, which are scattered all over the country, make it difficult.

Let’s hope this study works, or at least gives us valuable information to apply to the much larger population (about 95 percent) of those with Alzheimer’s disease without a clear-cut genetic trigger.